There are no clinically recognizable mechanisms associated with AD progression. Recent studies of elderly normal (NL) subjects show that individuals with increased levels of plasma amyloid beta 1-40 (A[unreadable]40) are at higher risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). In transgenic AD (Tg) and wild type mice models, elevated plasma A[unreadable]40 is associated with decreased hippocampal (HIP) vasoreactivity (VR) and in Tg even prior to A[unreadable] deposits or brain damage. Our human pilot data in support of these animal findings suggest that plasma A[unreadable]40 is a biologically active vasoconstrictor of cerebral blood vessels, with pronounced early effects on HIP VR. However, it remains unclear if reduced VR is near the source of a clinical cascade that includes progressive structural brain damage, amyloid and tau pathology, and cognitive impairment. A vascular mechanism influencing progression is intriguing and consistent with the neuropathology and the epidemiology. However, since both plasma A[unreadable]40 and cardiovascular disease (CVD) impair brain endothelial and smooth muscle cell function, it is crucial to evaluate both factors and their interaction longitudinally. Our pilot data also show that A[unreadable]40 and CVD-risk independently target VR-CO2 affecting both overlapping and different cerebrovascular regions. The combined effects of elevated plasma A[unreadable]40 and CVD-risk on cognition, brain structure, and AD biomarkers remains unknown. We propose two NL aging studies. In Part 1 we will retrospectively establish the longitudinal relationships between plasma A[unreadable]40, CVD-risk, and cognitive decline in a large random community sample. We will assay plasma A[unreadable]40 and A[unreadable]42 levels in 1875 stored plasma samples from 625 randomly selected community residing NL elderly subjects, studied annually over a 3-year interval. In Part 2, we will conduct a prospective 2-year, three time point, longitudinal study of 200 NL individuals stratified by A[unreadable]40 level and CVD-risk. We will examine the relationships between A[unreadable]40 and CVD- risk factors as predictors of reduced VR-CO2 and AD related changes. All the required clinical, MRI, and biomarker measures were tested and validated during the funded cycle. This includes a new arterial spin labeling (ASL) method that precisely measures HIP and cortical perfusion and VR-CO2 without the spatial distortions typical in conventional echo-planar ASL. We will test four major hypotheses in cross-section and longitudinally: 1) elevations in plasma A[unreadable]40 levels preferentially reduce VR-CO2 in AD-vulnerable regions;2) elevated plasma A[unreadable]40, in association with reduced VR-CO2, predict a cascade of clinical and biological changes related to AD;3) elevated CVD-risk predicts reduced neocortical VR-CO2, and progressive deficits in verbal fluency and working memory;4) for subjects with combined risks of CVD and high plasma A[unreadable]40, there is a synergistic decrease in VR-CO2 and increased cognitive and structural brain changes. This study has the potential to reveal an AD-related vascular mechanism associated with progression and to improve our understanding of the interactions between AD and CVD. PUBLIC HEALTH RELEVANCE: Elevated plasma amyloid beta 1-40 (A[unreadable]40) levels in the elderly increase the risk of future memory impairment and Alzheimer's disease (AD). Our proposed MRI study of normal elderly will examine the hypothesis that plasma A[unreadable]40 is a vasoconstrictor of hippocampal and other cerebral blood vessels that impairs vasodilation and leads to progressive AD-related changes. This project could lead to new blood and MRI assessments for AD-risk, direct attention to modulating A[unreadable]40, and improve our mechanistic understandings of the known interactions between AD and other diseases that affect vascular function.